Imine chemistry plays a pivotal role in producing biologically active amine compounds. F. A. Davis, P. Zhou, B. C. Chen, Chem. Soc. Rev. 1998, 27, 13-18). The asymmetric nucleophilic addition reaction on imines produces a wide variety of chiral amine containing moieties. F. A. Davis, B. Yang, J. Am. Chem. Soc. 2006, 127, 8938-8407; F. A. Davis, R. E. Reddy, J. M. Szewczyk, G. V. Reddy, P. S. Potonovo, H. Zhang, D. T. Reddy, P. Zhou, P. Carroll, J. Org. Chem. 1997, 62, 2555-2563; D. A. Cogan, G. C. Liu, K. J. Kim, B. J. Backes, J. A. Ellman, J. Am. Chem. Soc. 1998, 120, 8011-8019; D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1999, 121, 268-269; D. J. Weix, Y. L. Shi, J. A. Ellman, J. Am. Chem. Soc. 2005, 127, 1092-1093, X. Han, D. Krishnamurthy, P. Grover, Q. K. Fang, C. H. Senanayake, J. Am. Chem. Soc. 2002, 124, 7880-7881; J. G. Ruano, I. Fernandez, M. del P. Catalina, A. A. Cruz, Tetrahedron Asymm., 1996, 7, 3407-3414; X. W. Sun, M. H. Xu, G. Q. Lin, Org. Lett. 2006, 8, 4979-4982; C. H. Zhao, L. Liu, D. Wang, Y. J. Chen, Eur. J. Org. Chem. 2006, 2977-2986; D. H. Hua, S. W. Miao, J. S. Chen, S. Iguchi, J. Org. Chem. 1991, 56, 4-6). For example, nucleophilic addition of boronates unto imines produces the essential precursor for the synthesis of bortezomib (Velcade), the first FDA approved proteasome inhibitor drug. Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910. Nucleophilic addition of cyanides unto imines produces natural and unnatural α-amino acids, and these are very useful building blocks for the synthesis of polypeptides. (R)-cetirizine dihydrochloride is used for the treatment of allergies, and it can be synthesized in high enantiopurity with the help of imine chemistry. Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2002, 43, 923. Aryl Grignard addition to imines is one of the key steps to synthesis of tubulin polymerization inhibitor (S)—N-acetylcolchinol. Besong, G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol. Chem. 2006, 4, 2193. In addition, there are several pharmacologically and biologically important compounds containing amine functionalities, wherein imine chemistry provides easy access to synthesize key precursors, and as a result to achieve the synthesis of target molecules. Davis, F. A., Deng, J., Org. Lett. 2005, 7(4), 621; Pflum, D. A. et al., Tetra. Lett. 43 (2002) 923.
With this interest, chiral N-phosphonylimines were developed and utilized in several asymmetric nucleophilic addition reactions such as aza-Henry, aza-Darzen, etc. to achieve excellent diastereoselectivities. A. Kattuboina, P. Kaur, T. Ai, G. Li, Chem. Biol. & Drug Design, 2008, 71, 216; A. Kattuboina, G. Li, Tetrahedron Lett. 2008, 49, 1573.
Later, research was conducted on further simplifying the imine chemistry by means of easy purification methods. In this process, the Group Assistant Purification (GAP) concept was developed, in which the addition reaction products are purified by simple washing with minimum amounts of solvents such as pentane, hexanes, heptane, ethyl acetate, etc. or mixture of solvents, depending on the solubility nature of the impurities and side products. Kaur, P.; Nguyen, T.; Li, G. Eur. J. Org. Chem. 2009, 912; Han, J.; Ai, T.; Li, G. Synthesis 2008, 16, 2519; Han, J.; Chen, Z.-X.; Ai, T.; Li, G. Chem. Biol. Drug Des. 2009, 73, 203; Chen, Z.-X.; Ai, T.; Kaur, P.; Li, G. Tetrahedron Lett. 2009, 50, 1079; Ai, T.; Li, G. Bioorg. Med. Chem. Lett. 2009, 19, 3967; Kaur, P.; Shakya, G.; Sun, H.; Pan, Y.; Li, G. Org. Biomol. Chem. 2010, 8, 1091; Ai, T.; Han, J.; Chen, Z. X.; Li, G. Chem. Biol. Drug. Des. 2009, 73, 203; Kattuboina, A.; Kaur, P.; Ai, T.; Li, G. Chem. Biol. Drug Des. 2008, 71, 216; Ai, T.; Pindi, S.; Kattamuri, P. V.; Li, G. Sci. China Series B: Chem. 2010, 53, 125; Pindi, S.; Kaur, P.; Shakya, G.; Li, G. Chem. Biol. Drug Design, 2011, 75, 20.